Executive Summary / Key Takeaways

• Summit Therapeutics has fundamentally transformed its focus to oncology through the in-licensing of ivonescimab, a novel PD-1/VEGF bispecific antibody, positioning it as the core asset for future growth.
• Ivonescimab possesses a differentiated technological design, including cooperative binding and a tetravalent structure, intended to enhance tumor targeting, improve efficacy, and manage the safety profile compared to existing therapies.
• The company is executing a multi-pronged Phase III clinical strategy in non-small cell lung cancer (NSCLC) with three global trials (HARMONi, HARMONi-3, HARMONi-7), targeting significant market opportunities and aiming for potential registration.
• Recent positive data from partner Akeso's trials in China (HARMONi-2, HARMONi-6, HARMONi-A) and early Phase II signals in other solid tumors provide crucial validation and inform Summit's expanding development plans beyond NSCLC.
• Summit maintains a solid liquidity position, bolstered by recent financing and debt repayment, providing runway to advance its clinical programs, though significant future capital will be required to fund potential milestones and commercialization.

The Transformation of Summit Therapeutics

Summit Therapeutics has undergone a significant strategic pivot, transitioning from a focus primarily on anti-infectives to becoming a dedicated oncology biopharmaceutical company. This transformation is centered entirely around ivonescimab, a novel bispecific antibody in-licensed from Akeso, Inc. through a landmark agreement signed in late 2022. This transaction marked the acquisition of a pivotal asset, granting Summit exclusive development and commercialization rights for ivonescimab across key territories including the United States, Canada, Europe, Japan, and more recently, Latin America, the Middle East, and Africa. The company's operations are now singularly focused on advancing this promising candidate through rigorous clinical development with the explicit goal of addressing serious unmet medical needs in cancer.

The strategic rationale behind this pivot is rooted in the potential of ivonescimab's unique mechanism of action. It is designed as a single molecule that simultaneously targets two highly validated pathways in oncology: programmed cell death protein 1 (PD-1) and vascular endothelial growth factor (VEGF). By combining immunotherapy via PD-1 blockade with the anti-angiogenesis effects of an anti-VEGF compound, ivonescimab aims to enhance anti-tumor activity.

Technological Edge: The Differentiated Profile of Ivonescimab

Ivonescimab stands out due to its intentional technological design, specifically engineered using Akeso's Tetrabody technology. This results in a tetravalent structure with four binding sites, designed to potentially allow cooperative binding of its intended targets. In vitro studies conducted by Akeso suggest that the binding of PD-1 increases the binding affinity of VEGF, and vice versa. Specifically, Akeso's data indicates over 10-fold increased binding affinity to PD-1 in the presence of VEGF in vitro, and over fourfold increased binding affinity to VEGF in the presence of PD-1 in vitro.

This cooperative binding mechanism, coupled with the tetravalent structure, is hypothesized to direct ivonescimab more effectively to the tumor microenvironment (TME) where both PD-1 and VEGF are often co-expressed at higher levels compared to healthy tissue. The strategic intent behind this design is to improve upon the efficacy thresholds and potentially the side effect and safety profiles associated with combining separate PD-1 and VEGF inhibitors. While direct quantitative comparisons on clinical efficacy and safety versus combination therapies are still being established in ongoing trials, the preclinical and early clinical data suggest a differentiated profile that forms a core part of Summit's investment thesis.

Building the Pipeline: A Multi-Pronged Clinical Strategy

Summit's clinical development strategy for ivonescimab is ambitious and rapidly expanding, primarily focused on non-small cell lung cancer (NSCLC) but with clear intentions to explore other solid tumors. The company is currently sponsoring three global Phase III trials with potential registration intent:

• HARMONi (2L EGFRm NSCLC): This trial evaluates ivonescimab combined with chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who have progressed after treatment with a third-generation EGFR tyrosine kinase inhibitor (TKI). Positioned as a fast-to-market approach, this study completed enrollment in October 2024 and received FDA Fast Track designation. Topline results are expected in mid-2025. This trial leverages insights from Akeso's HARMONi-A study in China, which evaluated a similar patient population and led to NMPA approval in April 2025, providing a potential read-through for the global study. Historically, PD-1 inhibitors alone have struggled to show significant benefit in this specific patient population.
• HARMONi-3 (1L NSCLC + Chemo): This multi-regional trial compares ivonescimab plus platinum-based doublet chemotherapy against the current standard of care, pembrolizumab plus chemotherapy, in first-line metastatic NSCLC patients without driver mutations. Initially focused on squamous histology, the protocol was amended in Q4 2024 to include non-squamous patients, significantly expanding the addressable market for this study by two to three times. Enrollment is ongoing in both cohorts. Akeso's positive HARMONi-6 study results in first-line squamous NSCLC (ivonescimab + chemo vs. tislelizumab + chemo) provide validation for this approach, marking the first known Phase III trial in NSCLC to show significant improvement over a PD-1/PD-L1 inhibitor combined with chemotherapy in a head-to-head setting.
• HARMONi-7 (1L PD-L1 High NSCLC Mono): Initiated in early 2025 with site activation and enrollment beginning in the U.S., this global Phase III trial directly compares ivonescimab monotherapy against pembrolizumab monotherapy in first-line metastatic NSCLC patients with high PD-L1 expression. This head-to-head design is a direct response to the compelling PFS data from Akeso's HARMONi-2 study in China, which showed a statistically significant improvement for ivonescimab monotherapy over pembrolizumab monotherapy (HR 0.51). An early interim OS analysis requested by the NMPA showed a clinically meaningful positive trend favoring ivonescimab (HR 0.78 at 39% data maturity), further supporting the potential for an OS benefit in the adequately powered HARMONi-7 study.

Beyond NSCLC, Summit is actively exploring opportunities in other solid tumors. Leveraging Akeso's encouraging Phase II data in areas like microsatellite stable (MSS) colorectal cancer, PD-L1 low or negative triple-negative breast cancer, recurrent metastatic head and neck squamous cell carcinoma, perioperative NSCLC, and NSCLC with brain metastases, the company is evaluating its next steps for pipeline expansion. Collaborations, such as the strategic alliance with MD Anderson Cancer Center and the clinical trial collaboration with Pfizer (PFE) to evaluate ivonescimab with various ADCs, are key components of this strategy to accelerate development, explore novel combinations, and identify new opportunities for ivonescimab as a potential "platform blockbuster drug."

Competitive Landscape and Market Opportunity

The market for checkpoint inhibitors and anti-angiogenesis therapies in oncology is highly competitive, dominated by large pharmaceutical companies like Merck (MRK) with Keytruda, Pfizer, Gilead Sciences (GILD), and Johnson & Johnson (JNJ). These companies possess vast resources, established commercial infrastructures, and extensive pipelines. The NSCLC market alone is a significant opportunity, expected to approach $20 billion for checkpoint inhibitors, while the global market across all checkpoint inhibitor indications is estimated to reach $90 billion.

Summit's competitive positioning is predicated on ivonescimab's differentiated mechanism and the potential for superior efficacy and/or a more manageable safety profile compared to existing monotherapies or combinations. While larger competitors benefit from economies of scale and broader portfolios, Summit aims to carve out market share through targeted development in specific patient populations and tumor types where ivonescimab's unique properties may offer an advantage. The head-to-head trials against pembrolizumab and tislelizumab are direct challenges to established standards of care, aiming to demonstrate clinical superiority. Furthermore, early data in settings like MSS colorectal cancer and PD-L1 low/negative TNBC, where PD-1 therapies have historically shown limited efficacy, highlight ivonescimab's potential to expand the addressable market beyond the current checkpoint inhibitor landscape.

Summit's smaller scale compared to its large-cap competitors translates to higher R&D intensity relative to its current lack of revenue and potentially higher per-unit manufacturing costs until scale is achieved. However, its focused strategy and agility in pursuing novel combinations and indications, as evidenced by the rapid expansion of its Phase III program and collaborations, are key strengths. The company is also building its commercial capabilities, having recently appointed a Chief Commercial Officer and key personnel, in preparation for potential future launches.

Financial Health and Outlook

Summit Therapeutics ended the first quarter of 2025 with a solid cash and short-term investments balance totaling approximately $361.3 million. This position was strengthened by a $235 million private placement in September 2024 and the full repayment of outstanding promissory notes by October 2024, rendering the company debt-free.

Operating expenses have increased significantly as the company ramps up its global Phase III clinical trials and builds its organizational infrastructure. Research and development expenses rose to $51.2 million in Q1 2025 from $30.9 million in Q1 2024, driven by increased clinical trial costs for ivonescimab and higher personnel expenses. General and administrative expenses also increased to $15.6 million from $11.5 million in the same period, reflecting investments in the executive team and professional services. This resulted in a net loss of $62.9 million for Q1 2025, compared to $43.5 million for Q1 2024. Cash used in operating activities was $61.2 million in Q1 2025.

Management has guided that the current cash position is sufficient to fund operating needs for at least the next 12 months from the May 1, 2025 filing date. However, the company expects to continue incurring significant operating losses for the foreseeable future. Future capital requirements are substantial, driven by the costs and timing of ongoing and planned clinical trials, potential regulatory filings, commercialization activities, and significant potential milestone payments to Akeso (up to $4.56 billion in regulatory and commercial milestones, plus royalties). Summit is actively evaluating various financing options to support its long-term goals.

Risks and Challenges

Despite the promising potential, Summit faces significant risks inherent in biopharmaceutical development. Clinical trials may not achieve their primary endpoints or demonstrate a favorable safety profile, potentially delaying or preventing regulatory approval. The recent topline data from the HARMONi trial, while meeting the primary PFS endpoint, showed only a positive trend in OS, which could impact regulatory discussions and commercial potential in that specific indication. Competition in the oncology market is intense, and larger players could launch competing therapies or combinations that limit ivonescimab's market uptake. The company is dependent on its collaboration with Akeso for the ivonescimab asset and supply. Future financing needs introduce dilution risk for existing shareholders, and there is no guarantee that necessary capital will be available on favorable terms. Furthermore, the company is involved in litigation related to the initial financing for the Akeso license, which could result in unfavorable outcomes.

Conclusion

Summit Therapeutics has rapidly transformed into a focused oncology company centered around ivonescimab, a bispecific antibody with a potentially differentiated technological profile. The company is executing an aggressive clinical development strategy across multiple high-value NSCLC indications, supported by promising data from its partner Akeso and strategic collaborations aimed at exploring ivonescimab's potential in novel combinations and tumor types. While recent clinical data provides validation and upcoming catalysts, such as the HARMONi topline results and the initiation of new trials, offer significant potential upside, the company operates in a highly competitive landscape and will require substantial future capital to realize its ambitious goals. The investment thesis hinges on ivonescimab demonstrating clinical superiority or meaningful differentiation in ongoing and planned trials, translating into regulatory approvals and successful commercialization against established competitors.